Methods and apparatus for making particles using spray dryer and in-line jet mill

ABSTRACT

Methods and apparatus are provided for making particles comprising: (a) spraying an emulsion, solution, or suspension, which comprises a solvent and a bulk material (e.g., a pharmaceutical agent), through an atomizer and into a primary drying chamber, having a drying gas flowing therethrough, to form droplets comprising the solvent and bulk material dispersed in the drying gas; (b) evaporating, in the primary drying chamber, at least a portion of the solvent into the drying gas to solidify the droplets and form particles dispersed in drying gas; and (c) flowing the particles and at least a portion of the drying gas through a jet mill to deagglomerate or grind the particles. By coupling spray drying with “in-line” jet milling, a single step process is created from two separate unit operations, and an additional collection step is advantageously eliminated. The one-step, in-line process has further advantages in time and cost of processing.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a divisional of U.S. application Ser. No. 10/324,943,filed Dec. 19, 2002, now pending. That application is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] This invention is generally in the field of process equipment andmethods for making particles, and more particularly to methods ofdeagglomerating or grinding spray dried particles.

[0003] Spray drying is commonly used in the production of particles formany applications, including pharmaceuticals, food, cosmetics,fertilizers, dyes, and abrasives. Spray drying can be tailored to createa wide spectrum of particle sizes, including microparticles. Spray driedparticles are useful in a variety of biomedical and pharmaceuticalapplications, such as the delivery of therapeutic and diagnostic agents,as described for example in U.S. Pat. No. 5,853,698 to Straub et al.;U.S. Pat. No. 5,855,913 to Hanes et al.; and U.S. Pat. No. 5,622,657 toTakada et al. For these applications, microparticles having veryspecific sizes and size ranges often are needed in order to effectivelydeliver the active agents.

[0004] Particles may tend to agglomerate during their production andprocessing, thereby undesirably altering the effective size of theparticles, to the detriment of the particle formulation's performanceand/or reproducibility. In other circumstances, the particles made maysimply be larger than desired for a particular application. Therefore,after they are produced, particles may require additional processing forsize reduction and/or deagglomeration.

[0005] In one common approach, separate batch process steps are used.For example, particles are made by a known spray drying process,collected, and then ground in a second, separate step. Such a batchmethod, however, undesirably requires the use of a transfer step fromthe spray dryer to the mill, which, for an aseptic process, may bedifficult to perform. Such a batch process also requires two separatecollection steps that are both associated with a yield loss. It would bedesirable to provide a sterile particle production and milling processand to minimize product yield losses, reduce material transfer steps,reduce process time, and reduce production costs. In addition,laboratory scale methods for producing microparticle pharmaceuticalformulations may require several steps, which may not be readily orefficiently transferred to larger scale production. It would bedesirable for the microparticle production and deagglomeration (orgrinding) process to be adaptable for efficient, cost effective,commercial scale production.

SUMMARY OF THE INVENTION

[0006] Methods and apparatus are provided for making particles in anin-inline process comprising: (a) spraying an emulsion, solution, orsuspension, which comprises a solvent and a bulk material, through anatomizer and into a primary drying chamber having a drying gas inlet, adischarge outlet, and a drying gas flowing therethrough, to formdroplets comprising the solvent and the bulk material, wherein thedroplets are dispersed in the drying gas; (b) evaporating, in theprimary drying chamber, at least a portion of the solvent into thedrying gas to solidify the droplets and form particles dispersed in thedrying gas, the particles dispersed in the drying gas being afeedstream; and (c) flowing the particles of the feedstream through ajet mill to deagglomerate or grind the particles. This process usingspray drying coupled with “in-line” jet milling eliminates an aseptictransfer from the spray dryer to the jet mill (which would beparticularly important for making pharmaceutical formulations comprisingthe particles) and an additional collection step that would beassociated with a yield loss. The inline process can effectively cutprocessing time by at least one half compared to a two step process.

[0007] In a preferred embodiment of the method, step (c) is conducted todeagglomerate at least a portion of agglomerated particles, if any,while substantially maintaining the size and morphology of theindividual particles. Alternatively, step (c) can be conducted to grindthe particles.

[0008] Preferably, the feedstream of step (b) is directed through aparticle concentration means to separate and remove at least a portionof the drying gas from the feedstream. In one embodiment, the particleconcentration means comprises a cyclone separator. In one embodiment,the cyclone separates between about 50 and 100 vol. % of the drying gasfrom the particles.

[0009] In one embodiment of the method, the feedstream of step (b) isdirected, before step (c), through at least one secondary drying chamberin fluid communication with the discharge outlet of the primary dryingchamber to evaporate a second portion of the solvent into the dryinggas. In a preferred embodiment, the secondary drying chamber comprisestubing having an inlet in fluid communication with the discharge outletof the primary drying chamber, wherein the ratio of the cross-sectionalarea of the primary drying chamber to the cross-sectional area of thetubing is at least 4:3, and wherein the ratio of the length of thetubing to the length of the primary drying chamber is at least 2:1.

[0010] In another embodiment of the method, multiple nozzles are used instep (a) to introduce multiple emulsions, solutions, suspensions, orcombinations thereof.

[0011] In one embodiment, the bulk material comprises a pharmaceuticalagent. The pharmaceutical agent may be a therapeutic, a prophylactic, ora diagnostic agent. In one embodiment, the therapeutic or prophylacticagent comprises a hydrophobic drug and the particles are microsphereshaving voids or pores therein. In another embodiment, the bulk materialcomprises a diagnostic agent, such as an ultrasound contrast agent oranother agent for diagnostic imaging. In another embodiment, the bulkmaterial further comprises a shell forming material, such as a polymer(e.g., a biocompatible synthetic polymer), a lipid, a sugar, a protein,an amino acid, or a combination thereof.

[0012] In a preferred embodiment, the particles are microparticles. Inone embodiment, the microparticles comprise microspheres having voids orpores therein.

[0013] In one embodiment, the bulk material comprises a therapeutic orprophylactic agent. In one embodiment, the therapeutic or prophylacticagent comprises a hydrophobic drug and the particles are microsphereshaving voids or pores therein. In another embodiment, the bulk materialcomprises a diagnostic agent, such as an ultrasound contrast agent orother agent for diagnostic imaging.

[0014] In one embodiment, the method further comprises adding anexcipient material or pharmaceutical agent to the feedstream of step(b). For example, this could be done after the feedstream has flowedthrough a particle concentration means to separate and remove at least aportion of the drying gas from the feedstream. In another example, thiscould be done before the feedstream has flowed through a particleconcentration means to separate and remove at least a portion of thedrying gas from the feedstream. In a preferred embodiment, the excipientor pharmaceutical agent is in the form of a dry powder. Examples of theexcipient material include amino acids, proteins, polymers,carbohydrates, starches, surfactants, and combinations thereof.

[0015] In another aspect, a method is provided for making a dry powderblend. The method includes the steps of (a) spraying an emulsion,solution, or suspension, which comprises a solvent and a bulk material,through an atomizer and into a primary drying chamber having a dryinggas inlet, a discharge outlet, and a drying gas flowing therethrough, toform droplets comprising the solvent and the bulk material, wherein thedroplets are dispersed in the drying gas; (b) evaporating, in theprimary drying chamber, at least a portion of the solvent into thedrying gas to solidify the droplets and form particles dispersed in thedrying gas, the particles dispersed in the drying gas being afeedstream; (c) adding a dry powder excipient material to the feedstreamto form a blended feedstream; and (d) flowing the particles andexcipient material through a jet mill to deagglomerate or grind theparticles and excipient material. Preferably, the method includesdirecting the feedstream of step (b) through a particle concentrationmeans to separate and remove at least a portion of the drying gas fromthe feedstream. In one embodiment, the particles are microparticlescomprising a pharmaceutical agent and the excipient material is in theform of microparticles having a size that is larger than the size of themicroparticles comprising a pharmaceutical agent. In a preferredembodiment, step (d) is conducted to deagglomerate at least a portion ofagglomerated particles, if any, while substantially maintaining the sizeand morphology of the individual particles. In another embodiment, asecond pharmaceutical agent can be added in step (c), in place of or inaddition to the excipient.

[0016] In another aspect, an apparatus is provided for making particlesand deagglomerating or grinding them. In a preferred embodiment, theapparatus comprises: (a) an atomizer disposed for spraying an emulsion,solution, or suspension which comprises a solvent and a bulk material toform droplets of the solvent and the bulk material; (b) a primary dryingchamber having a drying gas inlet and a discharge outlet, the atomizerbeing located in the primary drying chamber which provides forevaporation of at least a portion of the solvent into the drying gas tosolidify the droplets and form particles dispersed in the drying gas;and (c) a jet mill having an inlet in fluid communication with thedischarge outlet primary drying chamber, the jet mill being operable toreceive the particles dispersed in at least a portion of the drying gasand grind or deagglomerate the particles.

[0017] In one embodiment, the apparatus further includes at least onesecondary drying chamber interposed between, and in fluid communicationwith, the discharge outlet of the primary drying chamber and the inletof the jet mill, which provides additional drying of the particles,i.e., provides for evaporation of a second portion of the solvent intothe drying gas. In one version, the secondary drying chamber comprisestubing having an inlet in fluid communication with the discharge outletof the primary drying chamber, wherein the ratio of the cross-sectionalarea of the primary drying chamber to the cross-sectional area of thetubing is at least 4:3, and wherein the ratio of the length of thetubing to the length of the primary drying chamber is at least 2:1.

[0018] In one embodiment, the apparatus also includes a particleconcentration means, such as a cyclone separator, to separate and removeat least a portion of the drying gas from the particles, wherein theparticle concentration means has a particle discharge outlet in fluidcommunication with the inlet of the jet mill.

[0019] In another embodiment, the apparatus further comprises acollection cyclone to separate the drying gas from the deagglomerated orground particles that are discharged from the jet mill. Optionally, theapparatus includes a control valve to control the flow rate of thedrying gas discharged from the collection cyclone, a control valve tocontrol the flow rate of the drying gas discharged from the particleconcentration means, or both of these control valves.

[0020] In one embodiment, the apparatus further comprises a means forintroducing an excipient material into the particles and drying gasflowing between the discharge outlet of the primary drying chamber andthe inlet of the jet mill. This apparatus can be used, for example, tomake a dry powder blend in a single step, i.e., without intermediatecollection and blending steps between spray drying and jet milling.

[0021] In one embodiment, the apparatus further comprises multiplenozzles to introduce separate emulsions, solutions, suspensions, orcombinations thereof into the primary drying chamber. The multiplenozzles of this apparatus can be used, for example, to introducematerials that comprise a pharmaceutical agent, an excipient, orcombinations thereof. The multiple nozzles can be used, for example, tospray the same material in order to increase the throughput or can beused to spray different materials in order to create dry powders thatare mixtures of different particles.

[0022] In another aspect, pharmaceutical compositions are provided.These compositions comprise particles or dry powder blends made by thespray drying and in-line jet milling methods described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023]FIG. 1 is a process flow diagram of one embodiment of a processfor making microparticles by spraying drying with in-line jet milling todeagglomerate or grind the microparticles.

[0024]FIG. 2 is a process flow diagram of one embodiment of a processfor making blends of microparticles by spray drying with in-lineexcipient feeding and in-line jet milling.

[0025]FIG. 3 is a cross-sectional view of a typical jet mill that can beincorporated into the in-line process for spray drying and jet milling.

DETAILED DESCRIPTION OF THE INVENTION

[0026] Process systems and methods have been developed for makingparticles, such as microparticles, by spray drying and thendeagglomerating or grinding the particles using an in-line jet mill. Bycoupling spray drying with “in-line” jet milling, a single step processis created from two separate unit operations, and an additionalcollection step is eliminated, which otherwise would be associated witha yield loss and possible aseptic transfer which would be undesirablefor pharmaceutical production. The one-step, in-line process has furtheradvantages in time and cost of processing. In an optional embodiment,the systems also provide in-line blending of an excipient material withthe particles.

[0027] The jet milling step beneficially lowers residual moisture andsolvent levels in the particles, leading to better stability andhandling properties for dry powder pharmaceutical formulations or otherdry powder forms comprising the particles.

[0028] As used herein, the term “in-line” refers to process equipment influid communication arranged and adapted to process the materials in acontinuous, sequential manner. That is, the particles being processedflow between and through the individual pieces of equipment, without anintervening collection step.

[0029] In a preferred embodiment the particles are microparticles.

[0030] In a preferred method, the microparticles comprise one or morepharmaceutical agents. In one embodiment, the microparticle is formedentirely of a pharmaceutical agent. In another embodiment, themicroparticle has a core of pharmaceutical agent encapsulated in ashell. In yet another embodiment, the pharmaceutical agent isinterspersed within the shell or matrix. In another embodiment, thepharmaceutical agent is uniformly mixed within the material comprisingthe shell or matrix. Optionally, the microparticles of any of theseembodiments can be blended with one or more excipients.

[0031] I. In-Line Methods and Apparatus for Making Particles

[0032] The methods include (a) spraying an emulsion, solution, orsuspension, which comprises a solvent and a bulk material, through oneor more atomizers and into a primary drying chamber having a drying gasinlet, a discharge outlet, and a drying gas flowing therethrough, toform droplets comprising the solvent and the bulk material, wherein thedroplets are dispersed in the drying gas; (b) evaporating, in theprimary drying chamber, at least a portion of the solvent into thedrying gas to solidify the droplets and form particles dispersed in thedrying gas, the particles dispersed in the drying gas being afeedstream; and (c) flowing the particles and at least a portion of thedrying gas of the feedstream through a jet mill to deagglomerate orgrind the particles. In a preferred embodiment, step (c) is conducted todeagglomerate at least a portion of agglomerated particles, if any,while substantially maintaining the size and morphology of theindividual particles. Alternatively, step (c) is conducted to grind theparticles.

[0033] In a preferred embodiment, the feedstream of step (b) is directedthrough a particle concentration means to separate and remove at least aportion of the drying gas from the feedstream. This provides aconcentration of solids in the dispersion entering the jet mill that ishigh enough to permit the jet mill to operate effectively as intended,i.e., to deagglomerate or grind the particles.

[0034] In another preferred embodiment, which can be used with orwithout the particle concentration means, the apparatus includes one ormore secondary drying chambers interposed between, and in fluidcommunication with, the discharge outlet of the primary drying chamberand the inlet of the jet mill. These secondary drying chambers provideadditional drying of the particles, that is, they provide time andvolume for evaporation of a second portion of the solvent into thedrying gas.

[0035] In yet another embodiment, which can be used with or without theparticle concentration means and with or without the secondary dryingchambers, the apparatus includes a means for introducing anothermaterial into the particles and drying gas flowing between the dischargeoutlet of the primary drying chamber and the inlet of the jet mill. Inone embodiment, this other material could be an excipient, a secondpharmaceutical agent, or a combination thereof. For example, a drypowder beta agonist could be introduced into a feed stream from a spraydryer that is producing microparticles containing a corticosteroid. Thisapparatus can be used, for example, to make a dry powder blend in asingle step, i.e., without an intermediate collection step between spraydrying and jet milling.

[0036]FIG. 1 illustrates one example of an in-line system, or apparatus,10 for making and jet-milling particles. A liquid feed (i.e., anemulsion, solution, or suspension, which comprises a solvent and a bulkmaterial) and an atomization gas (e.g., air, nitrogen, etc.) are fedthrough an atomizer 14. The atomized droplets of solvent and bulkmaterial are formed in the primary drying chamber 12. A drying gas isfed through an optional heater 18 and into a primary drying chamber 12.In the primary drying chamber, the droplets are dispersed in the dryinggas, and at least a portion of the solvent is evaporated into the dryinggas to solidify the droplets and form a feed a feedstream of particlesdispersed in the drying gas. This feedstream then exits the primarydrying chamber 12 through outlet 16 and enters (optional) secondarydrying apparatus 20, which includes a coiled tube through which thefeedstream flows. Upon exiting the secondary drying apparatus 20, thedispersion enters the cyclone separator 22, which serves to concentratethe particles. A portion of the drying gas is separated from thefeedstream and exits the top vent 23 of the cyclone separator 22. Theconcentrated particles/drying gas then exits the cyclone separator 22and flows into a jet mill 24. A grinding gas (e.g., dry nitrogen) alsois supplied to the jet mill 24. The jet mill 24 deagglomerates or grindsthe particles, depending, in part, on the operating parameters selectedfor the jet mill. The jet-milled particles dispersed in drying gas (andgrinding gas) then flow from the jet mill 24 to a collection cyclone 26.The jet-milled particles are collected in collection jar 28 or othersuitable apparatus, and the drying and grinding gases are exhausted fromthe system 10. The exhaust gas from the cyclones 22 and 26 typically isfiltered (filters not shown) before release from the system and/or intothe atmosphere.

[0037]FIG. 2 illustrates one example of an in-line system, or apparatus,40 for making particle blends. In the embodiment shown, particles aremade by spray drying, directly blended with an excipient using anin-line excipient feed device, and then the resulting blend isjet-milled using an in-line jet mill, to yield a highly uniform particleblend. The process is like that shown in FIG. 1, except an excipientmaterial (or pharmaceutical material or combination thereof) is added tothe particles/drying gas, after, or more preferably before, theparticles/drying gas flows through cyclone separator 22. The resultingmixture of particles, excipient material, and drying gas then flows intojet mill 24, where the mixture is deagglomerated or ground. Thejet-milled particle/excipient blend dispersed in drying gas then flowsfrom the jet mill 24 to a collection cyclone 26 and collected incollection jar 28. The drying gas and grinding gas are exhausted fromsystem 40, as described above.

[0038] Preferably, the methods and systems are adapted for makingpharmaceutical formulations comprising microparticles. Themicroparticles are made by spray drying, and the jet milling iseffective to deagglomerate or grind the microparticles. The jet-millingstep can advantageously reduce moisture content and residual solventlevels in the formulation through the addition of dry and solvent freegas directly to the jet mill (e.g., as grinding gas). The jet-millingstep also can improve the suspendability and wettability of the drypowder formulation (e.g., for better injectability) and give the drypowder formulation improved aerodynamic properties (e.g., for betterpulmonary delivery).

[0039] The use of a of a spray dryer with an in-line jet mill, asopposed to a two-step process of a spray drying followed by a separatejet milling process, advantageously improves yield, reduces time, andreduces cost.

[0040] Spray Drying

[0041] The particles are formed by a spray drying technique known in theart. For example, the particles can be produced using the spray dryingmethods and devices described, for example, in U.S. Pat. No. 5,853,698to Straub et al., U.S. Pat. No. 5,611,344 to Bernstein et al., U.S. Pat.No. 6,395,300 to Straub et al., and U.S. Pat. No. 6,223,455 toChickering III, et al., which are incorporated herein by reference.

[0042] As used herein (in the examples), the symbol “0” is used toindicate the term “diameter” for the object being described.

[0043] As used herein, the term “solvent” refers to the liquid in whichthe material forming the bulk of the spray dried particle is dissolved,suspended, or emulsified for delivery to the atomizer of a spray dryerand which is evaporated into the drying gas, whether or not the liquidis a solvent or nonsolvent for the material. Other volatilizablecomponents, such as a volatile salt, may be included in the bulkmaterial/liquid, and volatilized into the drying gas.

[0044] In one embodiment, microparticles are produced by dissolving apharmaceutical agent and/or shell material in an appropriate solvent,(and optionally dispersing a solid or liquid active agent, pore formingagent (e.g., a volatile salt), or other additive into the solutioncontaining the pharmaceutical agent and/or shell material) and thenspray drying the solution, to form microparticles. As defined herein,the process of “spray drying” a solution containing a pharmaceuticalagent and/or shell material refers to a process wherein the solution isatomized to form a mist and dried by direct contact with carrier gases.Using spray drying equipment available in the art, the solutioncontaining the pharmaceutical agent and/or shell material may beatomized into a drying chamber, dried within the chamber, and thencollected via a cyclone at the outlet of the chamber. Representativeexamples of types of suitable atomization devices include ultrasonic,pressure feed, air atomizing, and rotating disk. The temperature may bevaried depending on the solvent or materials used. The temperature ofthe inlet and outlet ports can be controlled to produce the desiredproducts. Multiple nozzles (or other atomization devices) can be used toallow for introduction of multiple emulsions, solutions, suspensions, orcombinations thereof into the primary drying chamber. The multiplenozzles can be used, for example, to introduce materials that comprise apharmaceutical agent, an excipient, or combinations thereof. In oneembodiment, the multiple nozzles are used to spray the same material(from each nozzle) in order increase process throughput of the material.In another embodiment, the multiple nozzles are used to spray differentmaterials (e.g., different materials from each nozzle), for example, inorder to create dry powders that are mixtures of different particles,e.g., composed of different materials.

[0045] The size of the particulates of pharmaceutical agent and/or shellmaterial is a function of the nozzle used to spray the solution of thepharmaceutical agent and/or shell material, nozzle pressure, thesolution and atomization flow rates, the pharmaceutical agent and/orshell material used, the concentration of the pharmaceutical agentand/or shell material, the type of solvent, the temperature of spraying(both inlet and outlet temperature), and the molecular weight of a shellmaterial such as a polymer or other matrix material. Generally, if apolymer is used the higher the molecular weight, the larger the particlesize, assuming the concentration is the same (because an increase inmolecular weight generally increases the solution viscosity). Particleshaving a target diameter between 0.5 μm and 500 μm can be obtained. Themorphology of these microparticles depends, for example, on theselection of shell material, concentration, molecular weight of a shellmaterial such as a polymer or other matrix material, spray flow, anddrying conditions.

[0046] In an optional embodiment, the apparatus further includes one ormore secondary drying chambers downstream from the primary dryingchamber to provide additional solvent removal. In one embodiment, thesecondary drying chamber comprises the drying apparatus described inU.S. Pat. No. 6,308,434 and U.S. Pat. No. 6,223,455, which are herebyincorporated by reference. The secondary drying chamber preferablycomprises tubing having an inlet in fluid communication with thedischarge outlet of the primary drying chamber, to evaporate a secondportion of the solvent into the drying gas, wherein the ratio of thecross-sectional area of the primary drying chamber to thecross-sectional area of the tubing is at least 4:3, and wherein theratio of the length of the tubing to the length of the primary dryingchamber is at least 2:1.

[0047] Particle Concentration Means and Process Control

[0048] The particle concentration means can be essentially any devicesuitable for concentrating the particles in the drying gas such that theparticles can be effectively jet milled, whether for grinding ordeagglomeration. Representative devices for concentrating the particlesin the drying gas include cyclone separators, gravity settling chambers(knock-out pots), electrostatic charge precipitators, impingementseparators, mechanical centrifugal separators and uniflow cyclones.

[0049] In a preferred embodiment, the particle concentration meansincludes at least one cyclone separator as known in the art, to separateand remove at least a portion of the drying gas from said particles. Ina typical embodiment, the cyclone separator consists of a verticalcylinder with a conical bottom. The particle/drying gas dispersionenters the cyclone through a tangential inlet near the top, entering ina vortical motion. The centrifugal force created causes the particles tobe thrown toward the wall, and the drying gas falls downward along thewall and then spirals upward through the center when it reaches thebottom, producing a double vortex. The particles fall by gravity to thebottom of the device. One skilled in the art can select the appropriatedimensions of the separator based, for example, on the flow rates of gasand particles, percentage of gas to be separated, system pressures,particle mass and size, etc.

[0050] For a particular system, successful operation requires balancingof the flows and pressures in the process equipment, such that jet millperformance is maximized, particle blowback from the jet mill isavoided, and clogging of the cyclone and/or jet mill is avoided. Forexample, as shown in FIG. 1 and FIG. 2, control of the flow through thesystem 10 or system 40 can be performed with the use of a control valve30 downstream from the collection cyclone 26 and/or a control valve 32downstream from the separator cyclone 22, either or both of which can beused to control the pressure on the systems. For example, by increasingthe backpressure on the system, more drying gas can be separated andexpelled through the top vent of the cyclone separator. Alternatively,less drying gas can be directed through the top vent of the cycloneseparator by lowering the backpressure on the system. Alternatively, thedrying gas exhausted through the cyclone separator can be in part orentirely redirected into the system downstream of the jet mill outlet.Optionally, fresh gas can be added into the system downstream of the jetmill outlet. Such redirected or added gases can be used to balancepressures in the process.

[0051] While a control valve is shown in FIGS. 1 and 2, other flowcontrolling devices known in the art can be used to control the systempressure and/or flow rate of drying gas discharged from the particleconcentration means or the collection cyclone. For example, the flowcontrolling devices could comprise a device selected from controlvalves, filters, regulators, orifices, and combinations thereof.

[0052] In one embodiment, the solids content of the feedstream(particles/drying gas) from the primary and secondary drying chambers isincreased by separating out between about 50 and 100 vol. %, morepreferably about 90 and 100 vol. %, of the drying gas, which is expelledthrough top vent 23. For example, in one embodiment, the flow rate ofthe particles/drying gas from the spray dryer is 52 CFM (1500 L/min.)and the flow rate of the particles/drying gas to the jet mill is 0.52CFM (15 L/min.). The system components would be sized to maintain theappropriate gas velocity throughout the process.

[0053] Jet Milling

[0054] As used herein, the terms “jet mill” and “jet milling” includeand refer to the use of any type of fluid energy impact mills,including, but not limited to, spiral jet mills, loop jet mills, hammermills, grinders, crushers, and fluidized bed jet mills, with or withoutinternal air classifiers. These mills are known in the art. The jet millis used to deagglomerate or to grind the particles.

[0055] As used herein, the term “deagglomerate” refers to the techniquefor substantially deagglomerating microparticle agglomerates that havebeen produced during or subsequent to formation of the microparticles,by bombarding the feed particles with high velocity air or other gas,typically in a spiral or circular flow. The jet milling processconditions can be selected so that the microparticles are substantiallydeagglomerated while substantially maintaining the size and morphologyof the individual microparticles, which can be quantified as providing avolume average size reduction of at least 15% and a number average sizereduction of no more than 75%.

[0056] As used herein, the terms “grind”, “ground”, or “grinding” refersto particle size reduction by fracture, e.g., conventional milling. Thatis, the particles and/or agglomerates are reduced in size withoutsubstantially maintaining the size and morphology of the individualmicroparticles. The process is characterized by the acceleration ofparticles in a gas stream to high velocities for impingement on otherparticles, similarly accelerated, or impingement on the walls of themill.

[0057] A typical spiral jet mill 50 is illustrated in FIG. 3. Particles,with or without drying gas, are fed into feed chute 52. Optionalinjection gas is fed through one or more ports 56. The particles areforced through injector 54 into chamber 58. The particles enter anextremely rapid vortex in the chamber 58, where they collide with oneanother until small enough to become sufficiently entrained in the gasstream to exit a central discharge port 62 in the jet mill by the gasstream (against centrifugal forces experienced in the vortex). Grindinggas (so-named whether the jet mill is used for grinding ordeagglomeration) is fed from port 60 into gas supply ring 61. Thegrinding gas then is fed into the chamber 58 via a plurality ofapertures; only two 63 a and 63 b are shown. Ground or deagglomeratedparticles are discharged from the jet mill 50.

[0058] The selection of the material forming the bulk of the particlesand the temperature of the particles in the jet mill are among thefactors that affect deagglomeration and grinding. Therefore, the jetmill optionally can be provided with a temperature control system. Forexample, the control system may heat the particles, rendering thematerial less brittle and thus less easily fractured in the jet mill,thereby minimizing unwanted size reduction. Alternatively, the controlsystem may need to cool the particles to below the glass transition ormelting temperature of the material, so that deagglomeration ispossible.

[0059] In a preferred embodiment, the particles are aseptically fed tothe jet mill, and a suitable gas, preferably dry nitrogen, is used toprocess the microparticles through the mill. Grinding and injection gaspressures can be adjusted as need, for example, based on the materialcharacteristics. Preferably, these gas pressures are between 0 and 10bar, more preferably between 2 and 8 bar. Particle throughput depends onthe size and capacity of the jet mill. The jet-milled particles can becollected by filtration or, more preferably, cyclone.

[0060] Jet milling the particles, in addition to providing the desiredlevel of deagglomeration or grinding, can also lower the residualsolvent and moisture levels in the particles or particle blend while inprocess (i.e., before collection), due to the addition of dry andsolvent free gas (e.g., as grinding gas, injection gas, or both)provided to the jet mill. To achieve reduced residual levels, theinjection/grinding gas preferably is a low humidity gas, such as drynitrogen. In one embodiment, the injection/grinding gas is at atemperature less than 100° C. (e.g., less than 75° C., less than 50° C.,less than 25° C., etc.).

[0061] Blending

[0062] In an optional embodiment, the process further includes blendingthe particles with another material (e.g., an excipient material, a(second) pharmaceutical agent, or a combination thereof), which can bein a dry powder form. The blending can be performed before jet millingas an in-line process, after jet milling, or both before and after jetmilling.

[0063] In a preferred embodiment, the blending is conducted in a singlestep process, such as an in-line process, as shown for example in FIG.2. This process comprises spray drying with in-line blending and in-linejet milling. The excipient material preferably is added to thefeedstream before it flows into the jet mill. The excipient material canbe introduced into the feedstream using essentially any suitableintroduction means known in the art. Non-limiting examples of suchintroduction means include screw or vibratory feed from a closed hopper,a venturi feed from a vented hopper, via a feedstream from one or moreother spray drying units making the excipient particles, or via afeedstream from one or more jet milling devices. One skilled in the artcan readily connect a feed source line using standard techniques andprovide the excipient feed material at a sufficient pressure to causethe material to flow into and combine with the drying gas and particles.

[0064] In another embodiment, the excipient material is blended with theparticles post-jet milling, in a batch or continuous process, includingan in-line process. The blending can be carried out using essentiallyany technique or device suitable for combining the microparticles withone or more other materials (e.g., excipients), preferably to achieveuniformity of blend.

[0065] Content uniformity of solid-solid pharmaceutical blends iscritical. Jet milling can be conducted on the microparticles beforeblending or as part of a single process (spray drying with in-lineblending and in-line jet milling) to enhance content uniformity.Jet-milling advantageously can provide improved wetting anddispersibility upon reconstitution of the blends. In addition, theresulting microparticle formulation can provide improved injectability,passing through the needle of a syringe more easily. Jet milling canprovide improved dispersibility of the dry powder, which provides forimproved aerodynamic properties for nasal or pulmonary administration.

[0066] Other Steps in the Process

[0067] The particles may undergo additional processing steps.Representative examples of such processes include lyophilization orvacuum drying to further remove residual solvents, temperatureconditioning to anneal materials, size classification to recover orremove certain fractions of the particles (i.e., to optimize the sizedistribution), compression molding to form a tablet or other geometry,and packaging. In one embodiment, oversized (e.g., 20 μm or larger,preferably 10 μm or larger) microparticles are separated from themicroparticles of interest. Some formulations also may undergosterilization, such as by gamma irradiation.

[0068] II. The Particles

[0069] The particles made by the processes described herein comprise abulk material. As used herein, the term “bulk material” includesessentially any material that can be provided in a solution, suspension,or emulsion, and then fed through an atomizer and dried to formparticles. In preferred embodiments, the bulk material is apharmaceutical agent, a shell material, or a combination of apharmaceutical agent and a shell material, as described herein.

[0070] Size and Morphology

[0071] The particles made by the in-line spray drying and jet millprocess can be of any size. As used herein, the term “particle” includesmicro-, submicro-, and macro-particles. Generally, the particles arebetween about 100 nm and 5 mm in diameter or in the longest dimension.In a preferred embodiment, the particles are microparticles, which arebetween 1 and 999 microns in diameter or in the longest dimension. Asused herein, the term “microparticle” includes microspheres andmicrocapsules, as well as microparticles, unless otherwise specified.Microparticles may or may not be spherical in shape. Microcapsules aredefined as microparticles having an outer shell surrounding a core ofanother material, such as a pharmaceutical agent. The core can be gas,liquid, gel, or solid. Microspheres can be solid spheres or can beporous and include a sponge-like or honeycomb structure formed by poresor voids in a matrix material or shell.

[0072] As used herein, the terms “size” or “diameter” in reference toparticles refers to the number average particle size, unless otherwisespecified. An example of an equation that can be used to describe thenumber average particle size is shown below:$\frac{\sum\limits_{i = 1}^{p}{n_{i}d_{i}}}{\sum\limits_{i = 1}^{p}n_{i}}$

[0073] where n=number of particles of a given diameter (d).

[0074] As used herein, the term “volume average diameter” refers to thevolume weighted diameter average. An example of equations that can beused to describe the volume average diameter is shown below:$\left\lbrack \frac{\sum\limits_{i = 1}^{p}{n_{i}d_{i}^{3}}}{\sum\limits_{i = 1}^{p}n_{i}} \right\rbrack^{1/3}$

[0075] where n=number of particles of a given diameter (d).

[0076] As used herein, the term “aerodynamic diameter” refers to theequivalent diameter of a sphere with density of 1 g/mL were it to fallunder gravity with the same velocity as the particle analyzed.Aerodynamic diameters can be determined on the dry powder using anAerosizer (TSI), which is a time of flight technique, or by cascadeimpaction or liquid impinger techniques.

[0077] Particle size analysis can be performed on a Coulter counter, bylight microscopy, scanning electron microscopy, transmittance electronmicroscopy, laser diffraction methods such as those using a MalvernMastersizer, light scattering methods or time of flight methods. Where aCoulter method is described, the powder is dispersed in an electrolyte,and the resulting suspension analyzed using a Coulter Multisizer IIfitted with a 50-μm aperture tube.

[0078] In one embodiment, the jet milling process described herein candeagglomerate agglomerated particles, such that the size and morphologyof the individual particles is substantially maintained. That is, acomparison of the particle size before and after jet milling should showa volume average size reduction of at least 15% and a number averagesize reduction of no more than 75%. It is believed that the jet millingprocesses will be most useful in deagglomerating particles having avolume average diameter or aerodynamic average diameter greater thanabout 2 μm.

[0079] In one embodiment, the particles are microparticles comprising apharmaceutical agent for use in a pharmaceutical formulation. Thesemicroparticles preferably have a number average size between about 1 and10 μm. In one embodiment, the microparticles have a volume average sizebetween 2 and 50 μm. In another embodiment, the microparticles have anaerodynamic diameter between 1 and 50 μm.

[0080] The pharmaceutical agent containing particles typically aremanufactured to have a size (i.e., diameter) suitable for the intendedroute of administration. Particle size also can affect RES uptake. Forintravascular administration, the particles preferably have a diameterof between 0.5 and 8 μm. For subcutaneous or intramuscularadministration, the particles preferably have a diameter of betweenabout 1 and 100 μm. For oral administration for delivery to thegastrointestinal tract and for application to other lumens or mucosalsurfaces (e.g., rectal, vaginal, buccal, or nasal), the particlespreferably have a diameter of between 0.5 μm and 5 mm. A preferred sizefor administration to the pulmonary system is an aerodynamic diameter ofbetween 1 and 5 μm, with an actual volume average diameter (or anaerodynamic average diameter) of 5 μm or less.

[0081] In one embodiment, the particles comprise microparticles havingvoids therein.

[0082] In one embodiment, the microparticles have a number average sizebetween 1 and 3 μm and a volume average size between 3 and 8 μm.

[0083] Pharmaceutical Agents

[0084] The pharmaceutical agent is a therapeutic, diagnostic, orprophylactic agent. The pharmaceutical agent is sometimes referred toherein generally as a “drug” or “active agent.” The pharmaceutical agentin the final powder may be present in an amorphous state, a crystallinestate, or a mixture thereof.

[0085] A wide variety of drugs can be loaded into the microparticles.These can be small molecules, proteins or peptides, carbohydrates,oligosaccharides, nucleic acid molecules, or other synthetic or naturalagents. Examples of suitable drugs include the classes and species ofdrugs described in Martindale, The Extra Pharmacopoeia, 30th Ed. (ThePharmaceutical Press, London 1993). The drug can be in any suitableform, including various salt forms, free acid forms, free base forms,and hydrates.

[0086] In one embodiment, the pharmaceutical agent is a contrast agentfor diagnostic imaging. For example, the agent could be a gas forultrasound imaging, as described for example in U.S. Pat. No. 5,611,344to Bernstein et al., which is incorporated herein by reference. Otherexamples of suitable diagnostic agents useful herein include thoseagents known in the art for use in positron emission tomography (PET),computer assisted tomography (CAT), single photon emission computerizedtomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI).

[0087] In other embodiments, the pharmaceutical agent is a therapeuticor prophylactic agent. Non-limiting examples of these agents includewater soluble drugs, such as ceftriaxone, ketoconazole, ceftazidime,oxaprozin, albuterol, valacyclovir, urofollitropin, famciclovir,flutamide, enalapril, mefformin, itraconazole, buspirone, gabapentin,fosinopril, tramadol, acarbose, lorazepan, follitropin, glipizide,omeprazole, fluoxetine, lisinopril, tramsdol, levofloxacin, zafirlukast,interferon, growth hormone, interleukin, erythropoietin, granulocytestimulating factor, nizatidine, bupropion, perindopril, erbumine,adenosine, alendronate, alprostadil, benazepril, betaxolol, bleomycinsulfate, dexfenfluramine, diltiazem, fentanyl, flecainid, gemcitabine,glatiramer acetate, granisetron, lamivudine, mangafodipir trisodium,mesalamine, metoprolol fumarate, metronidazole, miglitol, moexipril,monteleukast, octreotide acetate, olopatadine, paricalcitol, somatropin,sumatriptan succinate, tacrine, verapamil, nabumetone, trovafloxacin,dolasetron, zidovudine, finasteride, tobramycin, isradipine, tolcapone,enoxaparin, fluconazole, lansoprazole, terbinafine, pamidronate,didanosine, diclofenac, cisapride, venlafaxine, troglitazone,fluvastatin, losartan, imiglucerase, donepezil, olanzapine, valsartan,fexofenadine, calcitonin, or ipratropium bromide.

[0088] Other examples include hydrophobic drugs such as celecoxib,rofecoxib, paclitaxel, docetaxel, acyclovir, alprazolam, amiodaron,amoxicillin, anagrelide, aripiprazole, bactrim, biaxin, budesonide,bulsulfan, carbamazepine, ceftazidime, cefprozil, ciprofloxicin,clarithromycin, clozapine, cyclosporine, diazepam, estradiol, etodolac,famciclovir, fenofibrate, fexofenadine, gemcitabine, ganciclovir,itraconazole, lamotrigine, loratidine, lorazepam, meloxicam, mesalamine,minocycline, modafinil, nabumetone, nelfinavir mesylate, olanzapine,oxcarbazepine, phenytoin, propofol, ritinavir, risperidone, SN-38,sulfamethoxazol, sulfasalazine, tacrolimus, tiagabine, tizanidine,trimethoprim, valium, valsartan, voriconazole, zafirlukast, zileuton,and ziprasidone. In this embodiment, the particles made by the processesdescribed herein preferably are porous.

[0089] In one embodiment, the pharmaceutical agent is for pulmonaryadministration. Non-limiting examples include corticosteroids such asbudesonide, fluticasone propionate, beclomethasone dipropionate,mometasone, flunisolide, and triamcinolone acetonide; other steroidssuch as testosterone, progesterone, and estradiol; leukotrieneinhibitors such as zafirlukast and zileuton; antibiotics such ascefprozil, amoxicillin; antifungals such as ciprofloxacin, anditraconazole; bronchiodilators such as albuterol, formoterol andsalmeterol; antineoplastics such as paclitaxel and docetaxel; andpeptides or proteins such as insulin, calcitonin, leuprolide,granulocyte colony-stimulating factor, parathyroid hormone-relatedpeptide, and somatostatin.

[0090] Examples of preferred drugs include aripirazole, risperidone,albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol,amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride,valrubicin, albendazole, conjugated estrogens, medroxyprogesteroneacetate, nicardipine hydrochloride, zolpidem tartrate, amlodipinebesylate, ethinyl estradiol, omeprazole, rubitecan, amlodipinebesylate/benazepril hydrochloride, etodolac, paroxetine hydrochloride,paclitaxel, atovaquone, felodipine, podofilox, paricalcitol,betamethasone dipropionate, fentanyl, pramipexole dihydrochloride,Vitamin D₃ and related analogues, finasteride, quetiapine fumarate,alprostadil, candesartan, cilexetil, fluconazole, ritonavir, busulfan,carbamazepine, flumazenil, risperidone, carbemazepine, carbidopa,levodopa, ganciclovir, saquinavir, amprenavir, carboplatin, glyburide,sertraline hydrochloride, rofecoxib carvedilol, halobetasolproprionate,sildenafil citrate, celecoxib, chlorthalidone, imiquimod, simvastatin,citalopram, ciprofloxacin, irinotecan hydrochloride, sparfloxacin,efavirenz, cisapride monohydrate, lansoprazole, tamsulosinhydrochloride, mofafinil, clarithromycin, letrozole, terbinafinehydrochloride, rosiglitazone maleate, diclofenac sodium, lomefloxacinhydrochloride, tirofiban hydrochloride, telmisartan, diazapam,loratadine, toremifene citrate, thalidomide, dinoprostone, mefloquinehydrochloride, trandolapril, docetaxel, mitoxantrone hydrochloride,tretinoin, etodolac, triamcinolone acetate, estradiol, ursodiol,nelfinavir mesylate, indinavir, beclomethasone dipropionate, oxaprozin,flutamide, famotidine, nifedipine, prednisone, cefuroxime, lorazepam,digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin,tamoxifen citrate, nimodipine, amiodarone, budesonide, formoterol,flucasone propionate, salmeterol, and alprazolam.

[0091] Shell Material

[0092] The shell material can be a synthetic material or a naturalmaterial. The shell material can be water soluble or water insoluble.The particles can be formed of non-biodegradable or biodegradablematerials, although biodegradable materials are preferred, particularlyfor parenteral administration. Examples of types of shell materialsinclude, but are not limited to, polymers, amino acids, sugars,proteins, carbohydrates, and lipids. Polymeric shell materials can bedegradable or non-degradable, erodible or non-erodible, natural orsynthetic. Non-erodible polymers may be used for oral administration. Ingeneral, synthetic polymers are preferred due to more reproduciblesynthesis and degradation. Natural polymers also may be used. Naturalbiopolymers that degrade by hydrolysis, such as polyhydroxybutyrate, maybe of particular interest. The polymer is selected based on a variety ofperformance factors, including the time required for in vivo stability,i.e., the time required for distribution to the site where delivery isdesired, and the time desired for delivery. Other selection factors mayinclude shelf life, degradation rate, mechanical properties, and glasstransition temperature of the polymer.

[0093] Representative synthetic polymers are poly(hydroxy acids) such aspoly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolicacid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide),polyanhydrides, polyorthoesters, polyamides, polycarbonates,polyalkylenes such as polyethylene and polypropylene, polyalkyleneglycols such as poly(ethylene glycol), polyalkylene oxides such aspoly(ethylene oxide), polyalkylene terepthalates such as poly(ethyleneterephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters,polyvinyl halides such as poly(vinyl chloride), polyvinylpyrrolidone,polysiloxanes, poly(vinyl alcohols), poly(vinyl acetate), polystyrene,polyurethanes and co-polymers thereof, derivativized celluloses such asalkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, celluloseesters, nitro celluloses, methyl cellulose, ethyl cellulose,hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, celluloseacetate butyrate, cellulose acetate phthalate, carboxyethyl cellulose,cellulose triacetate, and cellulose sulphate sodium salt jointlyreferred to herein as “synthetic celluloses”), polymers of acrylic acid,methacrylic acid or copolymers or derivatives thereof including esters,poly(methyl methacrylate), poly(ethyl methacrylate),poly(butylmethacrylate), poly(isobutyl methacrylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecylacrylate) (jointly referred to herein as “polyacrylic acids”),poly(butyric acid), poly(valeric acid), andpoly(lactide-co-caprolactone), copolymers and blends thereof. As usedherein, “derivatives” include polymers having substitutions, additionsof chemical groups, for example, alkyl, alkylene, hydroxylations,oxidations, salt formations, and other modifications routinely made bythose skilled in the art.

[0094] Examples of preferred biodegradable polymers include polymers ofhydroxy acids such as lactic acid and glycolic acid, and copolymers withPEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyricacid), poly(valeric acid), poly(lactide-co-caprolactone), blends andcopolymers thereof.

[0095] Examples of preferred natural polymers include proteins such asalbumin and prolamines, for example, zein, and polysaccharides such asalginate, cellulose and polyhydroxyalkanoates, for example,polyhydroxybutyrate. The in vivo stability of the matrix can be adjustedduring the production by using polymers such as polylactide-co-glycolidecopolymerized with polyethylene glycol (PEG). PEG, if exposed on theexternal surface, may extend the time these materials circulate, as itis hydrophilic and has been demonstrated to mask RES(reticuloendothelial system) recognition.

[0096] Examples of preferred non-biodegradable polymers include ethylenevinyl acetate, poly(meth)acrylic acid, polyamides, copolymers andmixtures thereof.

[0097] Bioadhesive polymers of particular interest for use in targetingof mucosal surfaces include, but are not limited to, polyanhydrides,polyacrylic acid, poly(methyl methacrylates), poly(ethyl methacrylates),poly(butylmethacrylate), poly(isobutyl methacrylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecylacrylate).

[0098] Representative amino acids that can be used in the shell includeboth naturally occurring and non-naturally occurring amino acids. Theamino acids can be hydrophobic or hydrophilic and may be D amino acids,L amino acids or racemic mixtures. Amino acids that can be used include,but are not limited to, glycine, arginine, histidine, threonine,asparagine, aspartic acid, serine, glutamate, proline, cysteine,methionine, valine, leucine, isoleucine, tryptophan, phenylalanine,tyrosine, lysine, alanine, and glutamine. The amino acid can be used asa bulking agent, or as an anti-crystallization agent for drugs in theamorphous state, or as a crystal growth inhibitor for drugs in thecrystalline state or as a wetting agent. Hydrophobic amino acids such asleucine, isoleucine, alanine, glucine, valine, proline, cysteine,methionine, phenylalanine, tryptophan are more likely to be effective asanticrystallization agents or crystal growth inhibitors. In addition,amino acids can serve to make the shell have a pH dependency that can beused to influence the pharmaceutical properties of the shell such assolubility, rate of dissolution or wetting.

[0099] The shell material can be the same or different from theexcipient material, if present. In one embodiment, the excipient cancomprise the same classes or types of material used to form the shell.In another embodiment, the excipient comprises one or more materialsdifferent from the shell material. In this latter embodiment, theexcipient can be a surfactant, wetting agent, salt, bulking agent, etc.In one embodiment, the formulation comprises (i) microparticles thathave a core of a drug and a shell comprising a sugar or amino acid,blended with (ii) another sugar or amino acid that functions as abulking or tonicity agent.

[0100] Excipients

[0101] For particles to be used in pharmaceutical applications, the term“excipient” refers to any non-active ingredient of the formulationintended to facilitate delivery and administration by the intendedroute. For example, the excipient can comprise amino acids, sugars orother carbohydrates, starches, surfactants, proteins, lipids, orcombinations thereof. The excipient may enhance handling, stability,aerodynamic properties and dispersibility of the active agent.

[0102] In preferred embodiments, the excipient is a dry powder (e.g., inthe form of microparticles), which is blended with drug microparticles.Preferably, the excipient microparticles are larger in size than thepharmaceutical microparticles. In one embodiment, the excipientmicroparticles have a volume average size between about 10 and 1000 μm,preferably between 20 and 200 μm, more preferably between 40 and 100 μm.

[0103] Representative amino acids that can be used in the drug matricesinclude both naturally occurring and non-naturally occurring aminoacids. The amino acids can be hydrophobic or hydrophilic and may be Damino acids, L amino acids or racemic mixtures. Non-limiting examples ofamino acids that can be used include glycine, arginine, histidine,threonine, asparagine, aspartic acid, serine, glutamate, proline,cysteine, methionine, valine, leucine, isoleucine, tryptophan,phenylalanine, tyrosine, lysine, alanine, glutamine. The amino acid canbe used as a bulking agent, or as a crystal growth inhibitor for drugsin the crystalline state or as a wetting agent. Hydrophobic amino acidssuch as leucine, isoleucine, alanine, glucine, valine, proline,cysteine, methionine, phenylalanine, tryptophan are more likely to beeffective as crystal growth inhibitors. In addition, amino acids canserve to make the matrix have a pH dependency that can be used toinfluence the pharmaceutical properties of the matrix such assolubility, rate of dissolution, or wetting.

[0104] Examples of excipients include pharmaceutically acceptablecarriers and bulking agents, including sugars such as lactose, mannitol,trehalose, xylitol, sorbitol, dextran, sucrose, and fructose. Othersuitable excipients include surface active agents, dispersants, osmoticagents, binders, disintegrants, glidants, diluents, color agents,flavoring agents, sweeteners, and lubricants. Examples include sodiumdesoxycholate; sodium dodecylsulfate; polyoxyethylene sorbitan fattyacid esters, e.g., polyoxyethylene 20 sorbitan monolaurate (TWEEN™ 20),polyoxyethylene 4 sorbitan monolaurate (TWEEN™ 21), polyoxyethylene 20sorbitan monopalmitate (TWEEN™ 40), polyoxyethylene 20 sorbitanmonooleate (TWEEN™ 80); polyoxyethylene alkyl ethers, e.g.,polyoxyethylene 4 lauryl ether (BRIJ™ 30), polyoxyethylene 23 laurylether (BRJ™ 35), polyoxyethylene 10 oleyl ether (BRIJ™ 97); andpolyoxyethylene glycol esters, e.g., poloxyethylene 8 stearate (MYRJ™45), poloxyethylene 40 stearate (MYRJ™ 52), Spans, Tyloxapol or mixturesthereof.

[0105] Examples of binders include starch, gelatin, sugars, gums,polyethylene glycol, ethylcellulose, waxes and polyvinylpyrrolidone.Examples of disintegrants (including super disintegrants) includestarch, clay, celluloses, croscarmelose, crospovidone and sodium starchglycolate. Examples of glidants include colloidal silicon dioxide andtalc. Examples of diluents include dicalcium phosphate, calcium sulfate,lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch andpowdered sugar. Examples of lubricants include talc, magnesium stearate,calcium stearate, stearic acid, hydrogenated vegetable oils, andpolyethylene glycol.

[0106] The amounts of excipient for a particular formulation depend on avariety of factors and can be selected by one skilled in the art.Examples of these factors include the choice of excipient, the type andamount of drug, the microparticle size and morphology, and the desiredproperties and route of administration of the final formulation.

[0107] In one embodiment for injectable microparticles, a combination ofmannitol and TWEEN™ 80 is blended with polymeric microspheres. In onecase, the mannitol is provided at between 50 and 200% w/w, preferably 90and 130% w/w, microparticles, while the TWEEN™ 80 is provided at between0.1 and 10% w/w, preferably 2.0 and 5.1% w/w microparticles. In anothercase, the mannitol is provided with a volume average particle sizebetween 10 and 500 μm.

[0108] In another embodiment, the excipient comprises lactose for aninhaled dosage form.

[0109] In yet another embodiment, the excipient comprises binders,disintegrants, glidants, diluents, color agents, flavoring agents,sweeteners, and lubricants for a solid oral dosage form such as acapsule, a tablet, or a wafer.

[0110] For particles to be used in non-pharmaceutical applications, theterm “excipient” refers to essentially any material that can be blendedwith the particles for any purpose.

[0111] III. Use of the Particles

[0112] Particles made using the processes described herein can be usedin a wide variety of applications and industries, including abrasives,agricultural products, biochemical products, chemicals, cosmetics, dyes,foods, metals, pigments, and pharmaceuticals. For some applications, theparticles preferably are microparticles.

[0113] In a preferred embodiment, the particles are microparticles foruse in a pharmaceutical formulation, which can be administered to ahuman or animal in need thereof, for the delivery of a therapeutic,diagnostic, or prophylactic agent in an effective amount. Theformulations can be administered in dry form or dispersed in aphysiological solution for injection or oral administration. The dryform can be aerosolized and inhaled for pulmonary administration. Theroute of administration depends on the pharmaceutical agent beingdelivered.

[0114] In one embodiment, microparticles or blends ofmicroparticles/excipient are jet milled to deagglomerate the particlesand then further processed, using known techniques, into a solid oraldosage form. Examples of such solid oral dosage forms includepowder-filled capsules, tablets, and wafers. The jet-millingadvantageously can provide improved wetting and dispersibility upon oraldosing as a solid oral dosage form formed from these microparticles ormicroparticle/excipient blends.

[0115] The invention can further be understood with reference to thefollowing non-limiting examples.

EXAMPLE 1 Spray Drying of PLGA Microspheres Without Milling (ComparativeExample)

[0116] This example describes a process for making PLGA microspheres.The microspheres were made in a batch spray drying process. A polymeremulsion was prepared, composed of droplets of an aqueous phasesuspended in a continuous polymer/organic solvent phase. The polymer wasa commercially obtained poly(lactide-co-glycolide) (PLGA) (50:50). Theorganic solvent was methylene chloride. The resulting emulsion was spraydried on a custom spray dryer with a dual drying chamber set-up. Theprocess conditions resulted in a theoretical solids to drying gas massflow ratio of 4.77 g solids/min.: 1.6 kg nitrogen/min. The outlettemperature of the primary drying chamber was maintained at 12° C. Thedischarge of the primary drying chamber was connected to a customsecondary drying chamber comprising 100 feet of 1.5″ Ø coiled tubing,enveloped by a water-cooled jacket. The discharge of the secondarydrying chamber was connected to a cyclone collector having a 1″ Ø inlet,a 1″ Ø exhaust outlet, and a 1.5″ Ø dust outlet. Three replicate batcheswere generated. Particle size was measured using a Coulter Multisizer IIwith a 50 μm aperture. Table 1 presents the average size results for thethree batches. TABLE 1 Particle Size of Unmilled PLGA MicrospheresExperiment Number Avg. Volume Avg. No. Particle Size, X_(n) (μm)Particle Size, X_(v) (μm) 1.1 2.5 ± 0.1 6.5 ± 0.1

EXAMPLE 2 PLGA Microparticles Formed Using an In-Line Spray Drying/JetMilling Process

[0117] PLGA microspheres were produced using a batch spray dryingprocess with an in-line jet mill. A polymer emulsion was prepared,composed of droplets of an aqueous phase suspended in a continuouspolymer/organic solvent phase. The polymer was a commercially obtainedpoly(lactide-co-glycolide) (PLGA) (50:50). The organic solvent wasmethylene chloride. The resulting emulsion was spray dried on a customspray dryer with a dual drying chamber set-up. The process conditionsresulted in a theoretical solids to drying gas mass flow ratio of 4.77 gsolids/min: 1.6 kg nitrogen/min. The outlet temperature of the primarydrying chamber was maintained at 12° C. The discharge of the primarydrying chamber was connected to a secondary drying chamber comprising100 feet of 1.5″ Ø coiled tubing, enveloped by a water-cooled jacket.The discharge of the secondary drying chamber was connected to aconcentrating cyclone having a 1″ Ø inlet, a 1″ Ø exhaust outlet, and a1.5″ Ø dust outlet. A 0.2 μm filter was attached to each of theconcentrating cyclone exhausts. A jet mill (Hosokawa 50AS) was connectedto the concentrating cyclone dust outlet using a 1.5″×2″ short reducer.Dry nitrogen was supplied to the jet mill for grinding and injectiongas. The jet mill was operated at Pi=3 bar and Pg=2.9 bar. A cyclonecollector, having a 3/8″ Ø inlet, a 3/4″ Ø exhaust outlet, and a 3/4″ Ødust outlet, was connected to the discharge of the jet mill to collectthe microspheres. A 0.2 μm filter was attached to the jet mill cycloneexhaust. This experiment was conducted in triplicate. An average productyield of 56.5±4.2% was obtained. Particle size was measured using thesame method as in Example 1, and the average results for the threebatches are shown in Table 2. TABLE 2 Particle Size of In-Line JetMilled PLGA Microspheres Experiment Number Avg. Volume Avg. No. ParticleSize, X_(n) (μm) Particle Size, X_(v) (μm) 2.1 2.3 ± 0.1 4.9 ± 0.1

[0118] Table 3 provides a comparison of the average size results of theunmilled and in-line milled microspheres from Examples 1 and 2. TABLE 3Size Comparison of PLGA Microspheres Experiment Number Avg. Volume Avg.No. Particle Size, X_(n) (μm) Particle Size, X_(v) (μm) 1.1 2.5 ± 0.16.5 ± 0.1 2.1 2.3 ± 0.0 4.8 ± 0.1

[0119] This demonstrates that in-line jet milling was effective indeagglomeration.

EXAMPLE 3 Batch Processing of Celecoxib Microspheres (ComparativeExample)

[0120] Celecoxib (CXB) microspheres were produced using a batch spraydrying process. A solution containing CXB in 800 mL of methanol-water(65:35) was spray dried on a custom spray dryer with a single dryingchamber. The process conditions resulted in a theoretical solids todrying gas mass flow ratio of 0.24 g solids/min: 1.7 kg nitrogen/min.The outlet temperature of the drying chamber was set at 20° C. Thedischarge of the drying chamber was connected to a cyclone collectorhaving a 1″ Ø inlet, a 1″ Ø exhaust outlet, and a 1.5″ Ø dust outlet.

[0121] Duplicate batches were generated. Yield was calculated as themass of dry product divided by the dry mass of non-volatile materials inthe feed stock. Geometric particle size (volume mean) was measured usingan Aerosizer particle sizer set at both high shear and zero shear. Table4 presents the yield and size results for the two batches. TABLE 4 Yieldand Particle Size Analysis of Unmilled CXB Microspheres Vol. Avg.Particle Vol. Avg. Particle Experiment Process Size, High Shear, Size,Zero Shear, No. Yield (%) X_(v) (μm) X_(v) (μm) 3.1 68% 6.2 6.0 3.2 76%5.4 6.3 Avg. 72% 5.8 6.2

[0122] The powder from Experiment No. 3.1 was fed manually into a FluidEnergy Aljet Jet-O-Mizer jet mill at a feed rate of about 1 g/min. Drynitrogen gas was used to drive the jet mill. The operating parameterswere 4 bar grinding gas pressure and 8 bar injection gas pressure. Acyclone collector, having a ⅜″×¾″ rectangular inlet, a ¾″ Ø exhaustoutlet, and a ½″ Ø dust outlet, was connected to the discharge of thejet mill to collect the microspheres. Yield and particle size weremeasured using the same methods as described above within the Example.Table 5 compares the results of the pre-milled material (Experiment No.3.1) to the results of the batch jet milled material (Experiment No.3.3). TABLE 5 Comparison of Unmilled and Batch Milled CXB MicrospheresVol. Avg. Particle Vol. Avg. Particle Experiment Process Size, HighShear, Size, Zero Shear, No. Yield (%) X_(v) (μm) X_(v) (μm) 3.1 68% 6.26.0 3.3 77% 3.3 3.4

[0123] The data shows that jet milling reduced the particle size of theCXB powder. The final yield of the batch process can be calculated bymultiplying the yield for experiment 3.1 times the yield from experiment3.2. This calculates to a final process yield of 52% for the batchmilled product.

EXAMPLE 4 Celecoxib Microspheres Formed Using an In-Line Process

[0124] CXB microspheres were produced using a spray drying process withan in-line jet mill. A solution containing CXB in 800 mL ofmethanol-water (65:35) was spray dried on a custom spray dryer with asingle drying chamber. The process conditions resulted in a theoreticalsolids to drying gas mass flow ratio of 0.24 g solids/min.: 1.7 kgnitrogen/min. The outlet temperature of the drying chamber was set at20° C. The discharge of the drying chamber was connected to aconcentrating cyclone having a 1″ Ø inlet, a 1″ Ø exhaust outlet, and a1.5″ Ø dust outlet. A jet mill (Fluid Energy Aljet Jet-O-Mizer) wasconnected directly to the concentrating cyclone dust outlet. Drynitrogen was supplied to the jet mill for grinding and injection gas.The jet mill was operated at Pi=8 bar and Pg=4 bar. This experiment wascarried out in duplicate, with different collection cyclones used ineach experiment. A cyclone collector, having a ⅜″×¾″ rectangular inlet,a 3/4″ Ø exhaust outlet, and a ½″ Ø dust outlet, was connected to thedischarge of the jet mill to collect the microspheres for Experiment No.4.1. A cyclone collector, having a 3/8″ Ø inlet, a ¾″ Ø exhaust outlet,and a ¾″ Ø dust outlet, was connected to the discharge of the jet millto collect the microspheres for Experiment No. 4.2. The small differencein yield between the two collection cyclones used in Experiments No. 4.1and No. 4.2 was not considered to be significant. Yield and particlesize were measured using the same methods as in Example 3. Table 6presents the average results for the duplicate batches. TABLE 6 Yieldand Particle Size of In-Line Jet Milled CXB Microspheres Vol. Avg.Particle Vol. Avg. Particle Experiment Process Size, High Shear, Size,Zero Shear, No. Yield (%) X_(v) (μm) X_(v) (μm) 4.1 64% 3.5 3.3

[0125] Table 7 provides a comparison of the average size and yieldresults of the unmilled, batch milled, and in-line milled CXBmicrospheres from Examples 3 and 4. TABLE 7 Comparison of CXBMicroparticles Vol. Avg. Particle Vol. Avg. Particle Experiment FinalProcess Size, High Shear, Size, Zero Shear, No. Yield (%) X_(v) (μm)X_(v) (μm) 3.2 72% 5.8 6.2 3.3 52% 3.3 3.4 4.1 64% 3.5 3.3

[0126] In-line jet milling was as effective as batch jet milling inreducing particle size. The in-line process resulted in a higher productyield (64%) than the combination of the batch processes (52%).

EXAMPLE 5 Batch Processing of Paclitaxel Microspheres (ComparativeExample)

[0127] Paclitaxel (PXL) microspheres were produced using a batch spraydrying process. A solution containing PXL in 800 mL of ethanol-water(80:20) was spray dried on a custom spray dryer with a single dryingchamber. The process conditions resulted in a theoretical solids todrying gas mass flow ratio of 0.83 g solids/min: 2.0 kg nitrogen/min.The outlet temperature of the drying chamber was set at 57° C. Thedischarge of the drying chamber was connected to a cyclone collectorhaving a 1″ Ø inlet, a 1″ Ø exhaust outlet, and a 1.5″ Ø dust outlet.

[0128] One batch was generated. Yield was calculated as the mass of dryproduct divided by the dry mass of non-volatile materials in the feedstock. Geometric particle size (volume mean) was measured using aMastersizer particle size analyzer set at maximum pressure. Table 8presents the yield and size results. TABLE 8 Yield and Particle SizeAnalysis of Unmilled PXL Microspheres Experiment No. Process Yield (%)Vol. Avg. Particle Size, X_(v) (μm) 5.1 70% 1.67

[0129] The powder from Experiment No. 5.1 was fed manually into a FluidEnergy Aljet Jet-O-Mizer jet mill at a feed rate of about 1 g/min. Drynitrogen gas was used to drive the jet mill. The operating parameterswere 4 bar grinding gas pressure and 8 bar injection gas pressure. Acyclone collector, having a 3/8″ Ø inlet, a 3/4″ Ø exhaust outlet, and a¾″ Ø dust outlet, was connected to the discharge of the jet mill tocollect the microspheres. Yield and particle size were measured usingthe same methods as described above within the Example. Table 9 comparesthe results of the pre-milled material (Experiment No. 5.1) to theresults of the batch milled material (Experiment No. 5.2). TABLE 9Comparison of Unmilled and Batch Milled PXL Microspheres Experiment No.Process Yield (%) Vol. Avg. Particle Size, X_(v) (μm) 5.1 70% 1.67 5.270% 1.63

[0130] The data shows that, in this case, batch jet milling did notsignificantly change the particle size of the PXL powder. The finalyield of the batch process can be calculated by multiplying the yieldfor Experiment No. 5.1 times the yield from Experiment No. 5.2. Thiscalculates to a final process yield of 49% for the batch milled product.

EXAMPLE 6 Paclitaxel Microspheres Formed Using an In-Line Process

[0131] PXL microspheres were produced using a spray drying process withan in-line jet mill. A solution containing PXL in 800 mL ofethanol-water (80:20) was spray dried on a custom spray dryer with asingle drying chamber. The process conditions resulted in a theoreticalsolids to drying gas mass flow ratio of 0.83 g solids/min: 2.0 kgnitrogen/min. The outlet temperature of the drying chamber was set at57° C. The discharge of the drying chamber was connected to aconcentrating cyclone having a 1″ Ø inlet, a 1″ Ø exhaust outlet, and a1.5″ Ø dust outlet. A jet mill (Fluid Energy Aljet Jet-O-Mizer) wasconnected directly to the concentrating cyclone dust outlet. Drynitrogen was supplied to the jet mill for grinding and injection gas.The jet mill was operated at P_(i)=8 bar and P_(g)=4 bar. A cyclonecollector, having a 3/8″ Ø inlet, a 3/4″ Ø exhaust outlet, and a 3/4″ Ødust outlet, was connected to the discharge of the jet mill to collectthe microspheres for Experiment No. 6.1. Yield and particle size weremeasured using the same methods as in Example 5. Table 10 presents theresults. TABLE 10 Yield and Particle Size of In-Line Jet Milled PXLMicrospheres Experiment No. Process Yield (%) Vol. Avg. Particle Size,X_(v) (μm) 6.1 66% 1.46

[0132] Table 11 provides a comparison of the average size and yieldresults of the unmilled, batch milled, and in-line milled PXLmicrospheres from Examples 5 and 6. TABLE 11 Comparison of PXLMicroparticles Final Process Vol. Avg. Particle Size, Experiment No.Yield (%) High Shear, X_(v) (μm) 5.1 70% 1.67 5.2 70% 1.63 6.1 66% 1.46

[0133] In-line jet milling was more effective than batch jet milling inreducing particle size. The in-line process resulted in a higher productyield (66%) than the combination of the batch processes (49%).

EXAMPLE 7 PLGA Microparticles Formed, Blended with Mannitol/Tween 80,and Jet Milled Using an In-Line Process

[0134] PLGA microspheres were produced using a single in-line processinvolving spray drying, blending with Mannitol/Tween 80 powder, andjet-milling using the Hosokawa 50AS jet-mill. A polymer emulsion wasprepared, composed of droplets of an aqueous phase suspended in acontinuous polymer/organic solvent phase. The polymer was a commerciallyobtained poly(lactide-co-glycolide) (PLGA) (50:50). The organic solventwas methylene chloride. The resulting emulsion was spray dried on acustom spray dryer with a dual drying chamber set-up. The Mannitol/Tween80 powder was injected at the discharge of the secondary drying chamber(which is upstream from the concentrating cyclone having a 1″ Ø inlet, a1″ Ø exhaust outlet, and a 1.5″ Ø dust outlet) using a nitrogen feed.The dust outlet of the concentrating cyclone was connected to the inletof the jet-mill. Another cyclone collector, having a 1″ Ø inlet, a 1″ Øexhaust outlet, and a 1.5″ Ø dust outlet, was connected to the dischargeof the jet-mill to collect the product.

[0135] The experiment was conducted in duplicate. The particle size ofthe product obtained from this experiment is given in Table 12. TABLE 12Particle Size Results Experiment Number Avg. Particle Size, Volume Avg.Particle Size, No. X_(n) (μm) X_(v) (μm) 7.1 2.2 ± 0.06 5.3 ± 0.15 7.22.2 ± 0.06 5.5 ± 0.20

[0136] Three samples from Experiment No. 7.1 were reconstituted with 5ml of RO/DI water, which dissolved the Mannitol/Tween 80 powder. Themicrosphere mass for each vial was determined by filtering thereconstituted suspension and collecting the undissolved microspheres onthe filter. The mass of mannitol/Tween 80 was determined by lyophilizingthe filtered solution. The results are given in Table 13. TABLE 13Particle Size Results PLGA microsphere Mannitol/ Experiment No. mass(mg) Tween 80 mass (mg) 7.1, vial #1 206 220 7.1, vial #2 234 223 7.1,vial #3 216 232 Average ± S.D.    219 ± 14   225 ± 6 R.S.D. 6.4% 2.8%

[0137] The relative standard deviation (R.S.D.) values from the Table 13indicate that it was possible to achieve a uniform blend through anin-line process involving spray drying, blending, and jet milling.

[0138] Publications cited herein and the materials for which they arecited are specifically incorporated by reference. Modifications andvariations of the methods and devices described herein will be obviousto those skilled in the art from the foregoing detailed description.Such modifications and variations are intended to come within the scopeof the appended claims.

We claim:
 1. A method for making a dry powder blend comprising: (a)spraying an emulsion, solution, or suspension, which comprises a solventand a bulk material, through an atomizer and into a primary dryingchamber having a drying gas inlet, a discharge outlet, and a drying gasflowing therethrough, to form droplets comprising the solvent and thebulk material, wherein the droplets are dispersed in the drying gas; (b)evaporating, in the primary drying chamber, at least a portion of thesolvent into the drying gas to solidify the droplets and form particlesdispersed in the drying gas, the particles dispersed in the drying gasbeing a feedstream; (c) adding a dry powder material to the feedstreamto form a combined feedstream; and (d) flowing the combined feedstreamthrough a jet mill to deagglomerate or grind the particles and drypowder material of the combined feedstream.
 2. The method of claim 1,wherein after step (b) and before step (c) the feedstream is directedthrough a particle concentration means to separate and remove at least aportion of the drying gas from the feedstream.
 3. The method of claim 2,wherein the particle concentration means comprises at least one cycloneseparator.
 4. The method of claim 3, wherein the at least one cycloneseparator separates between about 50 and 100 vol. % of the drying gasfrom the particles.
 5. The method of claim 1, wherein the combinedfeedstream is directed through a particle concentration means toseparate and remove at least a portion of the drying gas from thecombined feedstream.
 6. The method of claim 5, wherein the particleconcentration means comprises at least one cyclone separator.
 7. Themethod of claim 1, wherein step (d) deagglomerates at least a portion ofagglomerated particles, if any, while substantially maintaining the sizeand morphology of the individual particles.
 8. The method of claim 1,wherein the particles comprise a pharmaceutical agent and the dry powdermaterial is selected from the group consisting of an excipient material,a second pharmaceutical agent, and combinations thereof.
 9. The methodof claim 1, wherein the particles are microparticles comprising apharmaceutical agent and the dry powder material is in the form ofmicroparticles having a size that is larger than the size of themicroparticles which comprise the pharmaceutical agent.
 10. The methodof claim 1, further comprising after step (b) and before step (c)flowing the feedstream through a jet mill to deagglomerate or grind theparticles.
 11. A method for making a dry powder pharmaceutical blendcomprising: (a) spraying an emulsion, solution, or suspension, whichcomprises a solvent and a bulk material which comprises a pharmaceuticalagent, through an atomizer and into a primary drying chamber having adrying gas inlet, a discharge outlet, and a drying gas flowingtherethrough, to form droplets comprising the solvent and the bulkmaterial, wherein the droplets are dispersed in the drying gas; (b)evaporating, in the primary drying chamber, at least a portion of thesolvent into the drying gas to solidify the droplets and formmicroparticles dispersed in the drying gas, the microparticles dispersedin the drying gas together forming a feedstream; (c) adding a dry powdermaterial to the feedstream to form a combined feedstream, the dry powdermaterial being selected from the group consisting of an excipientmaterial, a second pharmaceutical agent, and combinations thereof, and(d) flowing the combined feedstream through a jet mill to deagglomerateor grind the microparticles and dry powder material of the combinedfeedstream.
 12. The method of claim 11, wherein step (d) deagglomeratesat least a portion of agglomerated microparticles, if any, whilesubstantially maintaining the size and morphology of the individualparticles.
 13. The method of claim 11, wherein the dry powder materialis in the form of microparticles having a size that is larger than thesize of the microparticles which comprise the pharmaceutical agent. 14.An in-line process for making a dry powder blend comprising: (a)spraying an emulsion, solution, or suspension, which comprises a solventand a bulk material, through an atomizer and into a primary dryingchamber having a drying gas inlet, a discharge outlet, and a drying gasflowing therethrough, to form droplets comprising the solvent and thebulk material, wherein the droplets are dispersed in the drying gas; (b)evaporating, in the primary drying chamber, at least a portion of thesolvent into the drying gas to solidify the droplets and form particlesdispersed in the drying gas, the particles dispersed in the drying gasbeing a feedstream; (c) flowing the feedstream through a jet mill todeagglomerate or grind the particles; (d) adding a dry powder materialto the feedstream to form a combined feedstream; and (e) optionallyflowing the combined feedstream through a second jet mill todeagglomerate or grind the particles and dry powder material of thecombined feedstream.
 15. The process of claim 14, wherein the feedstreamis directed through a particle concentration means to separate andremove at least a portion of the drying gas from the feedstream.
 16. Theprocess of claim 15, wherein the particle concentration means comprisesat least one cyclone separator.
 17. The process of claim 14, wherein thecombined feedstream is directed through a particle concentration meansto separate and remove at least a portion of the drying gas from thecombined feedstream.
 18. The process of claim 17, wherein the particleconcentration means comprises at least one cyclone separator.
 19. Theprocess of claim 14, wherein step (c) or step (e) deagglomerate at leasta portion of agglomerated particles, if any, while substantiallymaintaining the size and morphology of the individual particles.
 20. Theprocess of claim 14, wherein the particles comprise a pharmaceuticalagent and the dry powder material is selected from the group consistingof an excipient material, a second pharmaceutical agent, andcombinations thereof.
 21. The process of claim 14, wherein the particlesare microparticles comprising a pharmaceutical agent and the dry powdermaterial is in the form of microparticles having a size that is largerthan the size of the microparticles which comprise the pharmaceuticalagent.
 22. A pharmaceutical composition comprising a dry powder blendmade the method of claim
 1. 23. A pharmaceutical blend made by claim 11.24. A pharmaceutical composition comprising a dry powder blend made theprocess of claim 14.